We propose to develop a novel family of probes that will allow neuroscientists to record from a large number of neurons, to precisely estimate the location and dipole strength of spiking neurons within the recording volume and, when combined with optogenetics, to manipulate the activity of a chosen subset of these neurons in space and time. We will significantly reduce the size and increase the density of electrode sites relative to the state of the art, thus enabling 3-D mapping of spiking neurons with a resolution approaching 5 % of the recording volume. These probes will give neuroscientists the power to investigate the structure and function of neural circuits where the local connections and functional properties of neurons can change in a few tens of microns; an example is cortical minicolumns where even basic questions about the size, constitution, and physiological properties have not been settled 60 years after their discovery. They can be implanted on the cortical surface as well as in deep brain structures such as the thalamus which plays a crucial role in the vision system and the hippocampus which is involved in learning, memory, addiction, and degenerative diseases of the brain (e.g. Parkinson's and Alzheimer's diseases). The fabrication of such powerful probes is now feasible due to the development of a unique toolset at the Nanosystems Manufacturing Center at UH that enables the integration of sub-micrometer thin film electrodes and associated interconnect wiring on the cylindrical surface of fine optical fibers with tight, 0.25 mm, manufacturing tolerances. The use of optical fibers as probe substrates provides high intensity, multi-spectral light delivery with essentially no coupling loss as well as the strength and stiffness required for deep-brain applications. The use of thin film conductors contributes negligibly to the probe diameter, high resolution permits a very high electrode count on thin fibers, and high dimensional precision enables accurate 3-D localization of neuronal sources. A second crucial development will be the design and implementation of a zero-insertion-force connector to interface thin- film wiring on the (cylindrical) probe and commercial neuro-amplifier/ signal processing systems. Specific Aim 1 - To optimize multi-channel probe and interface designs: We will develop probes designed for optimal spatial localization in sensing volumes at the tip and distributed along the shank of the probe. A zero- insertion-force connector will be developed capable of interfacing ~50-channel probes with commercial electronics. Design will follow the pioneering work of Mechler and Victor, which we will experimentally validate for the first time. Specific Aim 2 - To develop low cost, 2-dimensional probe arrays: We will develop linear optrode arrays to enable the direct perturbation of a neural population code and map long-range interactions causally rather than through correlations. Combined with the 3-D mapping of neuronal dipoles within this volume, these tools will provide unprecedented investigative capabilities to systems neuroscientists.